Familial hypercholesterolemia (FH) has a frequency of 0.2% in most populations of the world. In selected populations such as the Afrikaners in South Africa, the Christian Lebanese, and the French Canadians, the disease is more frequent due to the founder effect. Previous studies demonstrated that a single mutation at the LDL receptor locus, the so-called French Canadian deletion, makes up 60% of the mutant genes responsible for FH in the French Canadian population. In this study, efforts were directed to determine if there were other common LDL receptor mutations in this population. Three missense mutations were identified and each mutation was reproduced and expressed in vitro. Two of the three mutations result in the production of an LDL receptor protein that is not processed to its mature form at a normal rate. Molecular assays were developed to detect the mutations directly, and the LDL receptor genes of 130 French Canadian FH heterozygotes were screened for the presence of the three missense mutations as well as two deletions. LDL receptor mutations were detected in 76% of individuals and 14% had one of the three missense mutations. (J. Clin. Invest. 1990Invest. . 85:1014Invest. -1023.) familial hypercholesterolemia-LDL receptors hypercholesterolemia
Approximately 15% of patients treated for advanced head and neck cancer with surgery and radiotherapy will develop hypothyroidism. Those treated with total laryngectomy and radiotherapy are at greatest risk.
The development of severe secondary laryngeal changes in dogs aged six months or less supports the suggestion that immature brachycephalic dogs should undergo assessment and, if indicated, surgery as soon as any clinical signs of BAS are apparent.
In conclusion, Lym-1 had more potent direct and indirect cytotoxic effects than rituximab in lymphoma cells under conditions achievable in patients. Because the HLA-DR target antigen of Lym-1 is enriched on most B-cell lymphomas, these results support its complementary use in patients as an alternative to CD20 for monoimmunotherapy and for combination immunotherapy with rituximab, because the HLA-DR and CD20 antigens are physically and functionally coupled on human B cells.
RNA was isolated from 22 squamous cell carcinomas (SCCs) obtained from diverse sites within the head and neck and from matched normal tissue where available. Tissue samples were then screened for expression of RNA from tumor suppressor gene p16 by utilizing semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis. p16-Specific PCR amplification products generated from tumor samples were subject to further analysis by direct DNA sequencing to determine if any tumor sample harbored a p16 mutation. The results show the presence of mutations in 10 of 22 (45%) of the tumor samples. Mutations comprise two identical point mutations, two small deletions (1 bp and 2 bp), one single-nucleotide insertion, four larger deletions, and an insertion/deletion. No mutations in p16 have been identified by analysis of PCR products generated from normal matched tissue, suggesting that p16 alterations are generated by somatic mutation and are not germline in origin. All 22 samples were analyzed additionally by immunohistochemistry for nuclear expression of the retinoblastoma (RB) tumor suppressor gene product. Results show lack of RB nuclear expression in only one sample, suggesting that mutation of RB is an infrequent event in the development of SCC of the head and neck (SCCHN).
Purpose: Monoclonal antibodies (mAb) in combination and mAbs combined with a radionuclide (radioimmunotherapy) have both been more effective in patients than mAb monotherapy. Experimental Design: Using assays of cell growth and viability, the dose response and temporal characteristics of CD20 (rituximab) and HLA-DR (Lym-1) mAbs, singly and in combination, and of 90 Y-conjugated Lym-1mAb have been characterized in five human lymphoma cell lines (B35M, Raji, SU-DHL-4, SU-DHL-6, and Ramos) spanning Burkitt's to diffuselarge celllymphoma. Although Ramos had a lower HLA-DR density, these cell lines were otherwise selected because of high cell surface CD20 and HLA-DR abundance. Assays of cell growth and death were done using microscopy and trypan blue dye. Results: Lym-1and rituximab, used singly, showed direct antilymphoma effects; those of Lym-1 were often more potent than those of rituximab. Combinations of these mAbs were more effective, sometimes synergistic, than either mAb singly, even in more resistant SU-DHL-4 cells. Conjugation of 90 Y to Lym-1also augmented potency in all cell lines and overcame resistance to both Lym-1and rituximab in Ramos cells. Conclusions: Lym-1exhibited substantially greater direct antilymphoma effects than rituximab in lymphoma cells in culture. Combination of Lym-1 with rituximab or 90 Y increased potency and overcame treatment resistance in lymphoma cells. Greater use of combination therapies of this type to increase potency and range of effectiveness seems likely to improve patient outcome. Many antilymphoma monoclonal antibodies (mAb) have beenshown to have biological activity in vitro. Several have also been shown to be effective for immunotherapy and radioimmunotherapy in patients as single agents. The chimeric CD20 mAb, rituximab, induces responses in f50% of patients with lowgrade follicular lymphoma although even these patients may relapse and become resistant to rituximab monotherapy (1, 2). In patients with aggressive lymphoma, rituximab has a lower response rate. Combinations of other mAbs with rituximab have been shown to be effective in patients (3,4 Seattle, Washington), have proven more effective for therapy than the mAb alone (2, 5). This has also been shown to be the case for the HLA-DR mAb Lym-1 (6). CD20 and HLA-DR antigens are expressed on many B-cell lymphomas at high surface densities and not modulated following mAb binding. Further, there is evidence of physical as well as functional interactions between these antigens that are members of the superantigen family (7 -9). Finally, low-dose rate radiation, as from radionuclides, seems to operate through apoptotic mechanisms in common with mAb effects.We have shown that the HLA-DR mAb, Lym-1, was more potent than rituximab in some cell lines and complemented the potency of rituximab (10). These in vitro observations are supported by those made in patients for the combination of rituximab and Hu1D10, another mAb against the HLA-DR h subunit (3).The purpose of this publication is to report the results for c...
Rituximab is effective in about one half of patients with indolent lymphoma. Even these patients relapse and develop rituximab resistance. To increase potency and circumvent resistance, the anti-lymphoma effects of rituximab, an anti-CD20 MAb 1 , combined with chLym-1 2 , an anti-HLA-DR MAb, were assessed in human lymphoma cell lines by examining growth inhibition and cell death, apoptosis induction, ADCC 3 and CDC 4 . There were additive effects in all assays and synergism in cell lines, such as B35M, which displayed resistance to either MAb alone. In B35M cells, combined rituximab and chLym-1 induced a 27-fold direct reduction in viable cells, whereas equivalent concentrations of rituximab or chLym-1 alone induced only a 1-fold and 10-fold reduction in viable cells, respectively. Because these results occurred at MAb concentrations readily achievable in patients, they suggest that this combination immunotherapy regimen may increase the potency and range of effectiveness of these MAbs in lymphoma patients.
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